Severe injury triggers a state of immune suppression that predisposes the patient to infection and sepsis. Traumatic injury alters cytokine production by T cells from injured patients and experimentally injured animals. The mechanism for injury-induced effects on T cell mediated immunity is poorly understood. The applicant has demonstrated that therapy with cytokines or cytokine antagonists that correct burn injury induced effects on T cells that protect mice from developing immune suppression. The applicant proposes to use a state of the art approach to examine the in vivo mechanisms responsible for injury induced effects on T cells. The hypothesis is proposed that severe injury alters antigen-specific T cell activation, that naive T cells are affected differently than antigen activated T cells, and T cell costimulatory pathways are important in mediating these effects. The proposed experiments will use T cell receptor transgenic mice as a tool to dissect the effect of injury on T cell activation, differentiation, and deletion or expansion in vivo. Three specific aims are proposed: 1) to determine the effect of burn injury on naive and antigen-activated T cells in vivo; 2) to define the kinetics of burn injury effects on T cells in vivo; and, 3) to test the contribution that T cell costimulation makes to the injury-induced effects on T cells. The results of the experiments will provide insight into mechanisms responsible for injury-induced effects on the adaptive immune system and will contribute new information that may lead to the development of novel therapeutic approaches for preventing injury-induced immune suppression.